Selexipag is known chemically as 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, also named ACT-293987 or NS-304 (for convenience, it is also referred to NS-304 in the present invention.). Its structural formula is shown below:

NS-304 was invented by Nippon Shinyaku Co. Ltd., which had good prostacyclin (PGI2) receptor agonist activity and effects of inhibiting platelet aggregation, dilation of blood vessels, dilation of bronchial muscle, inhibiting lipid deposition and inhibiting leukocyte activation. Actelion Pharmaceuticals Co. Ltd. has submitted the new drug application of NS-304 as a pulmonary arterial hypertension (PAH) drug to U.S. FDA. Phase III clinical data showed that this oral drug could reduce the morbidity/mortality of pulmonary arterial hypertension patients by 39% compared with placebo.
Patent Document WO2002088084A1 first reported a preparation method of NS-304, which comprising the following steps: (1) reacting 2-chloro-5,6-diphenylpyrazine with 4-isopropylamino-1-butanol to obtain 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol; (2) reacting 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol with tert-butyl bromoacetate to obtain 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester; (3) hydrolyzing 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester to obtain 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid; (4) reacting 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid with 1,1-carbonyl diimidazole (CDI), then reacting with methanesulfonamide in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene to obtaine NS-304. The reaction formula is shown below:

In this preparation method, 2-chloro-5,6-diphenylpyrazine was used as the raw material to obtain NS-304 by the multi-step reaction, the total yield was only 26%. Especially, in the step (1), the reaction selectivity was poor, purification was difficult and the molar yield was only 56%. The product of the step (1), 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol, is an important intermediate in preparing of NS-304, its yield and purity can largely influence yield and purity of the final product which further may be difficult to achieve high quality requirements in pharmaceutical preparations. In addition, in steps (1), (2) and (4), silica gel column chromatography was needed in purification, which resulted in high cost, inefficiency, serious pollution and unsuitability for industrial production.
Patent Document CN102459198A reported another preparation method of NS-304, which comprising the following steps: (1) reacting 2-chloro-5,6-diphenylpyrazine with sodium iodide to obtain 2-iodo-5,6-diphenylpyrazine; (2) in the presence of an alkali, reacting 2-iodo-5,6-diphenylpyrazine with 4-isopropylamino-1-butanol in an organic solvent at 170-200° C. for 5-9 hours to obtain 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol, wherein the organic solvent was, for example, sulfolane, N-methylpyrrolidone, N,N-dimethyl imidazolidinone, dimethyl sulfoxide or a mixed solvent thereof; (3) reacting 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol with N-(chloroacetyl)methanesulfonamide to obtain NS-304. The reaction formula is shown below:

CN102459198A did not provide specific preparation examples, but the present inventors found some defects in this preparation method by studies. Strong polar organic solvents with high boiling points were used in the step (2), they were unstable during the long time reaction at high temperature of 170-200° C. and led to side reactions, post-treatment and separating of solvents and the product were difficult, a lot of water was needed to quench the reaction and waste water was difficult to handle; when placed in a high-temperature alkaline environment, the condensation reaction of 2-iodo-5,6-diphenylpyrazine may occur and produce lots of impurity S (its structural formula is shown below); in the step (2), the reaction had poor selectivity, low yield and high cost, column chromatography was needed in the separation process of post-treatment, it was unsuitable for industrial production. In addition, in the step (3), removing excessive N-(chloroacetyl)methanesulfonamide and purification of the product were difficult.
